PROJECT SUMMARY The goal of this application is two-fold. First, we will test and validate across two imaging sites a set of diagnostic and progression biomarkers we have recently published that differentiate and track disease progression in Parkinson's disease (PD), parkinsonian variant of multiple system atrophy (MSAp) and progressive supranuclear palsy (PSP). Second, we will use a set of novel imaging biomarkers to further understand the neurobiology of how each of these three diseases differ and progress over time. With respect to goal 1, over the past 5 years our group has led the efforts in magnetic resonance imaging (MRI) for the Parkinson's Disease Biomarker Program (PDBP) and has developed 2 innovative biomarkers for differentiating PD, MSAp, and PSP. Both free-water diffusion imaging and task-fMRI have uncovered clear patterns of degeneration and abnormal functional activation in the basal ganglia and cerebellum that can reliably differentiate PD, MSAp, and PSP. In longitudinal studies we found that free-water diffusion imaging and task- fMRI track progression of PD, MSAp, and PSP over one year with no changes in age and sex matched controls. Reproducible, reliable, objective and validated MRI-based progression markers are of great significance and would transform clinical trials in PD, MSAp, and PSP. With respect to goal 2, in addition to evaluating free-water and task-based fMRI using our standardized protocol across two imaging sites, we will also test new biomarkers that leverage advanced imaging pulse sequences using simultaneous multi-slice imaging for acquiring data faster and at a higher spatial resolution. Such technical advances provide a richer examination of the nigrostriatal, cortico-striatal, and cerebellar-thalamo-cortical anatomical tracts for disease differentiation, and for understanding how the disease spreads along disease-specific tracts over time. Leveraging simultaneous multi-slice imaging will facilitate multi-shell diffusion imaging models for examining free-water, neurite density and orientation dispersion, as well as task-fMRI connectivity for examining the functional connections across a network. At our two imaging sites, we will acquire data on 100 PD, 50 MSAp, 50 PSP, and 50 healthy age and sex matched controls. We will provide timely data sharing with the PDBP community. We have a very experienced team of experts in neurology and neuroimaging, and a long history of publishing together in high impact journals.